This is the only fully funded Specialized Research Center of the National Institute of Neurological Disease and Stroke on primary and metastatic brain tumors of adults and children. It is presently in its 10th year of funding and this application represents its third submission for competitive review and renewal. As detailed in the body of this application, both primary and metastatic tumors to the CNS remain as significant health problems and are actually increasing in magnitude. Despite intensive research efforts by many investigators there has been little progress made in uncovering etiology, or improving treatment of primary or metastatic brain tumors during the last 30 years. This Specialized Research Center on Primary and Malignant Tumors of the CNS will continue intensification of the brain tumor research efforts of an outstanding group of internationally recognized investigators with a long history of effective collaboration. They will approach primary and metastatic brain tumors in adults and children in areas of etiology, mechanisms of transformation and altered growth control, improved diagnosis, preclinical and clinical therapy. Projects range from basic mechanistic studies on etiology such as tumor suppressor genes in human medulloblastoma, discovery of new drugs and mechanisms of drug resistance, to selection of molecular targets against adult and childhood brain tumors for targeted therapy and growth inhibition. Specific development of targeted therapy with radiolabeled and toxin-conjugated; preclinical and clinical trials of regional or compartmental therapy with radiolabeled MAbs, toxin-conjugated MAbs, and new drugs will ultimately be combined in years 3-5 with Phase 2 and 3 studies of systemic therapy with regional and compartmental therapy to reach tumor cells in the entire neuraxis. We believe that during this five year grant period better control of local and distant recurrence of primary and metastatic brain tumors can be achieved, improvement can be made in therapy of neoplastic meningitis, and quality and quantity of survival of both groups of patients will be improved. Moreover, our basic studies should define new molecular targets for future approach in 5-10 years with additional targeted therapy such as gene therapy replacement of putative suppressor genes and gene therapy of other molecular targets involved in transformation and altered growth control.